Far from being a static archive of information, the genome is composed of dynamic molecules that fold, replicate, and respond to the chemistry of life. These processes, along with external stresses such as radiation or reactive molecules, expose DNA to wear and tear, creating damage that the cell must detect and repair to keep the genome intact. Among the most dangerous lesions are DNA double-strand breaks—cuts through the double helix that can lead to harmful rearrangements of chromosomes, mutations, or cell death if not repaired swiftly and precisely.
The most accurate way to fix such breaks is through homology-directed repair, a pathway in which the cell restores the missing information by copying it from an identical sequence, usually the sister chromatid. But finding this matching sequence within a genome that contains billions of DNA letters is a “needle-in-a-haystack” search.
Although scientists had identified many of the molecular tools involved in this repair pathway, how these tools find the right place to work inside the crowded nucleus was still unknown. Cohesin—a ring-shaped protein that holds sister chromatids together and folds DNA into loops—was known to be essential for the process, yet its role in guiding the homology search had not been resolved.
Researchers from the lab of Daniel Gerlich at IMBA have discovered how cohesin guides this homology search. Their study, published in the journal Science, reveals that cohesin operates in two coordinated modes during DNA repair: one remodels the surrounding chromatin to enlarge loops that define where the search takes place; the other keeps the broken DNA physically linked to its undamaged sister copy. Together, these mechanisms transform a daunting genome-wide quest into a focused and efficient search within the nucleus.
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Original Publication
“Cohesin guides homology search during DNA repair via loops and sister chromatid linkages.” Federico Teloni*, Zsuzsanna Takacs, Michael Mitter, Christoph C. H. Langer, Inès Prlesi, Thomas L. Steinacker, Vincent P. Reuter, Dmitry Mylarshchikov, and Daniel W. Gerlich*. Science, 2025. DOI: http://science.org/doi/10.1126/science.adw0566
*Corresponding authors.